The number of percutaneous coronary intervention (PCI) procedures, commonly known as balloon angioplasty, has increased by 30% over the past 10 years totaling more than 1.3 million patients in the U.S. annually at a cost of more than $60 billion [1]. However, PCI procedures are not without post-procedure complications including thrombosis and restenosis [2]. PCI procedures result in injury of the vessel wall, which in turn initiates inflammation and coagulation through platelet activation. Attenuating the inflammatory and coagulation responses can mitigate the negative impact of the injury [3-5]. Drug-eluting stents (DESs) have been used widely due to their ability to prevent restenosis. However, a complication of DESs is development of late in-stent thrombosis at the same rate as the bare metal stents (BMSs). The DESs used in clinical application deliver an anti-proliferative agent, such as sirolimus or paclitaxel (PTX), which inhibits not only smooth muscle cells (SMCs) proliferation, but also prevents proliferation of endothelial cells (ECs). Controlling the late thrombosis, which occurs between 1 month and 1 year after stenting, requires solving fundamental problems related to the lack of EC growth in the stented area, while maintaining the inhibition of intimal hyperplasia offered by the antiproliferative drug. The main objective of this project is to further develop our in vitro model of both normal and hyperplasic vessels [6], in order to test novel therapies that, in conjunction with stents, will control thrombosis and inflammation, and therefore, intimal hyperplasia, thus improving the outcomes for DESs. The hypothesis of this proposal is that the late in-stent thrombosis is largely due to the lack of growth of ECs over the stented area, and further, that both SMC proliferation and lack of EC growth can be controlled through early steps of preventing initial platelet binding, attenuating inflammation and limiting the SMC mitogenic response. To address this hypothesis we have developed four specific aims in which we will investigate the delivery of a peptide drug that has been designed to inhibit inflammation and restenosis without affecting EC migration and proliferation, and shown in vivo to inhibit intimal hyperplasia. We will couple release of this drug from a DES with a temporary monolayer coating of blood vessel with peptidoglycan (dermatan sulfate (DS)) conjugated with collagen-binding eicosapeptide, RRANAALKAGELYKSILYGC (abbreviated SILY)) that prevents platelet adhesion and activation in order to limit platelet activation and SMC proliferation leading to intimal hyperplasia and late-term thrombosis. Finally, we will deliver probucol to promote EC growth over the stented area. At the end of the proposed studies we will have a simple vessel coating approach and a DES targeted to inhibit SMC proliferation and promote reendothelialization that will have been evaluated for in vivo proof-of- concept and will be ready for extensive in vivo evaluation for improving the outcomes of PCI procedures. ! PUBLIC HEALTH RELEVANCE: The number of percutaneous coronary intervention (PCI) procedures, commonly known as balloon angioplasty, has increased by 30% over the past 10 years totaling more than 1.3 million patients in the U.S. annually at a cost of more than $60 billion [1]. However, a complication of drug-eluting stents (DESs) is development of late in-stent thrombosis because the drugs used inhibit not only smooth muscle cells proliferation, but also prevents proliferation of endothelial cells. This proposal focuses on new DESs that promote endothelialization while preventing intimal hyperplasia and thrombosis.